My research is focused on understanding neuronal mechanisms of synaptic plasticity involved in pain and drug addiction circuits. One area of current research is focused on identifying intracellular signaling pathways involved in morphine tolerance and dependence using in vitro brain-slice recordings and in vivo behavioral assays. Our experiments focus on how mu opioid receptors (MOPrs) in the periaqueductal gray area (PAG) modulate neuronal excitability and synaptic transmission of PAG neurons. MOPrs are an integral part of the endogenous descending antinociceptive pathway that decreases pain impulses in the spinal cord. Repeated and continuous opioid administration induces neural changes in this system. A second area of research in my laboratory is the dopamine transporter (DAT) and an associated chloride current that I identified in midbrain dopamine neurons. The DAT is one of a family of transporters that are the main targets for psychostimulants, such as amphetamine and cocaine. These transporters are also targets for therapeutic drugs for disorders including depression and attention deficit disorder. Although the transporters are primarily known for regulating extracellular concentrations of neurotransmitters through reuptake of released neurotransmitters, they have significant electrical activities as well. My recent studies determined that these transporters have a role in modulating excitability of midbrain neurons.
- B.A., Bowdoin College, Brunswick Maine 1990
- Ph.D., Oregon Health & Science University, Portland Oregon 1996
1. Underhill, S.M., Hullihen, P., Chen, J., Ferrer, C.F. ,Rizzo, M., Ingram, S.L. and Amara, S.G. (2019). Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains. Molecular Psychiatry, in press.
2. McPherson, K.B., Leff, E.R., Li, M-H., Meurice, C., Tai, S., Traynor, J.R., Ingram, S.L. (2018). Regulators of G protein Signaling (RGS) proteins promote receptor coupling to G protein-coupled inwardly-rectifying potassium (GIRK) channels. The Journal of Neuroscience, 38(41):8737-8744. PMCID in progress.
3. Underhill, S.M., Ingram, S.L., Ahmari, S.E., Veenstra-VanderWeele, J., Amara, S.G. (2018). Neuronal excitatory amino acid transporter EAAT3: Emerging functions in health and disease, Neurochemistry International, (18)30139-6. PMCID in progress.
4. Chen, Q., Roeder, Z., Li, M-H., Zhang, Y.M., Ingram, S.L., Heinricher, M.M. (2017). Optogenetic evidence for a direct circuit linking nociceptive transmission through the parabrachial complex with pain-modulating neurons of the rostral ventromedial medulla (RVM). eNeuro. 4(3). PMCID: PMC5483601
5. Li, M-H, Underhill, SM, Reed, C, Phillips, TJ, Amara, SG, Ingram, SL. (2017). Amphetamine and methamphetamine increase NMDAR-GluN2B synaptic currents in midbrain dopamine neurons. Neuropsychopharmacology, 42(7):1539-1547. PMCID: PMC5436114.
6. Li, M-H., Suchland, K.L. Ingram, S.L. (2017). Compensatory activation of cannabinoid CB2 receptor inhibition of GABA release in the rostral ventromedial medulla (RVM) in inflammatory pain. The Journal of Neuroscience, 37(3): 626-636.PMCID: PMC5242409
7. Tonsfeldt, K.J., Suchland, K.L., Beeson, K.A., Lowe, J.D., Li, M-H., Ingram, S.L. (2016). Sex differences in GABAA signaling in the periaqueductal gray Induced by persistent inflammation. The Journal of Neuroscience, 36(5): 1669-81. PMCID: PMC4737776
8. Bobeck, E.N., Ingram, S.L., Hermes, S.M., Aicher, S.A., Morgan, M.M. (2016). Ligand-biased activation of extracellular signal-regulated kinase 1/2 leads to differences in opioid induced antinociception and tolerance.Behavioral Brain Research, 298(Pt B): 17–24. PMCID: PMC4779316
9. Li, M-H., Suchland, K.L., Ingram, S.L. (2014). GABAergic transmission and enhanced modulation by opioids and endocannabinoids in adult rat rostral ventromedial medulla. Journal of Physiology, 593(1): 217-30. PMCID: PMC4293064.
10. Underhill, S.M., Wheeler, D.S., Li, M., Watts, S.D., Ingram, S.L., Amara, S.G. (2014). Amphetamine modulates glutamatergic neurotransmission through endocytosis of the excitatory amino acid transporter EAAT3 in dopamine neurons. Neuron, 83(2): 404-16. PMCID: PMC4159050.
- "Chronic psychostimulant exposure to adult, but not periadolescent rats reduces subsequent morphine antinociception" Pharmacology Biochemistry and Behavior June 2012
- "Efficacy and kinetics of opioid action on acutely dissociated neurons" Molecular Pharmacology July 1997
- "Cortistatin increase of a potassium conductance in rat locus coeruleus in vitro" British Journal of Pharmacology 1997
- "Contribution of adenylyl cyclase modulation of pre- and postsynaptic GABA neurotransmission to morphine antinociception and tolerance" Neuropsychopharmacology 2014
- "Modulation of the hyperpolarization-activated current (Ih) by cyclic nucleotides in guinea-pig primary afferent neurons" Journal of Physiology April 1 1996
- "Opioid inhibition of Ih via adenylyl cyclase" Neuron 1994
- "Opioid receptor internalization contributes to dermorphin-mediated antinociception" Neuroscience June 2010
- "Contribution of dopamine receptors to periaqueductal gray-mediated antinociception" Psychopharmacology June 2009
- "Pain" Current Biology February 3 2014
- "Functional characterization of rhesus embryonic stem cell-derived serotonin neurons" Experimental Biology and Medicine May 2010
- "Columnar distribution of catecholaminergic neurons in the ventrolateral periaqueductal gray and their relationship to efferent pathways" Synapse February 2013
- "Differential control of opioid antinociception to thermal stimuli in a knock-in mouse expressing regulator of G-protein signaling-insensitive GÎ±o protein" Journal of Neuroscience March 6 2013
- "Extracellular signal-regulated kinase 1/2 activation counteracts morphine tolerance in the periaqueductal gray of the rat" Journal of Pharmacology and Experimental Therapeutics November 2009
- "Dopamine transporter-mediated conductances increase excitability of midbrain dopamine neurons" Nature Neuroscience October 2002
- "Glutamate modulation of antinociception, but not tolerance, produced by morphine microinjection into the periaqueductal gray of the rat" Brain Research October 12 2009
- "Analgesic tolerance to microinjection of the Î¼-opioid agonist DAMGO into the ventrolateral periaqueductal gray" Neuropharmacology June 2007
- "Behavioral and electrophysiological evidence for opioid tolerance in adolescent rats" Neuropsychopharmacology March 2007
- "Chronic inflammatory pain prevents tolerance to the antinociceptive effect of morphine microinjected into the ventrolateral periaqueductal gray of the rat" Journal of Pain December 2013
- "Cellular and molecular mechanisms of opioid action" Progress in Brain Research 2000
- "Ligand-biased activation of extracellular signal-regulated kinase 1/2 leads to differences in opioid induced antinociception and tolerance" Behavioural Brain Research February 1 2016
- "The multiple LIM domain-containing adaptor protein Hic-5 synaptically colocalizes and interacts with the dopamine transporter" Journal of Neuroscience August 15 2002
- "Amphetamine Modulates Excitatory Neurotransmission through Endocytosis of the Glutamate Transporter EAAT3 in Dopamine Neurons" Neuron July 16 2014
- "Tolerance to the antinociceptive effect of morphine in the absence of short-term presynaptic desensitization in rat periaqueductal gray neurons" Journal of Pharmacology and Experimental Therapeutics December 2010
- "Potentiation of rabbit trigeminal responses to capsaicin in a low pH environment" Brain Research July 18 1994
- "Opioids, NSAIDS and 5-lipoxygenase inhibitors act synergistically in brain via arachidonic acid metabolism" Inflammation Research 1999
- "Enhanced opioid efficacy in opioid dependence is caused by an altered signal transduction pathway" Journal of Neuroscience December 15 1998
- "Regulation of Î¼-opioid receptors" Pharmacological Reviews 2013
- "Antinociceptive tolerance revealed by cumulative intracranial microinjections of morphine into the periaqueductal gray in the rat" Pharmacology Biochemistry and Behavior September 2006
- "Actions of the ORL1 receptor ligand nociceptin on membrane properties of rat periaqueductal gray neurons in vitro" Journal of Neuroscience 1997
- "Differential development of antinociceptive tolerance to morphine and fentanyl is not linked to efficacy in the ventrolateral periaqueductal gray of the rat" Journal of Pain August 2012